Malnutrition and cachexia are common in patients with advanced pancreatic ductal adenocarcinoma (PDAC) and have a significant influence on the tolerance and response to treatments. If timely identified, malnourished PDAC patients could be treated to increase their capacity to complete the planned treatments and therefore, possibly, improve their efficacy.

The aim of the study is to assess the impact of nutritional status, pancreatic exocrine insufficiency (PEI), and other clinical factors on patient outcomes in patients with advanced PDAC.

The nutritional status will be determined by means of Mini-Nutritional Assessment score and laboratory blood tests. PEI will be defined as the presence of typical symptoms and/or reduced fecal elastase. Analysis: chemotherapy dosing over the first 12 weeks of therapy (i.e. percent of chemotherapy received in the first 12 weeks, as defined above) PAC-MAIN will provide insights on the role of malnutrition and PEI in outcomes of PDAC.

Investigators hypothesize that malnutrition has an adverse impact on the clinical course of patients with advanced PDAC treated with chemotherapy.

Aims:

To investigate the association between the nutritional status and pancreatic exocrine function and the clinical outcomes of patients with advanced PDAC.

Study design:

The PAncreatic Cancer MAlnutrition and exocrine pancreatic INsufficiency in the course of chemotherapy in unresectable pancreatic cancer (PAC-MAIN) study is a non-profit, international, multicentre, prospective, observational, cohort study evaluating the effect of the nutritional status and pancreatic exocrine function on the main outcomes of patients with advanced PDAC. The study will be carried out in Russia, Turkey, Serbia, Romania, Italy, and Spain as a part of the Pancreas 2000 Educational Program. Pancreas 2000 is a post-graduate educational program that prepares young gastroenterologists, surgeons, radiologists, and other physicians for specialization in Pancreatology.

Patient-related:

• sex, race, age at diagnosis
• Mini-Nutritional Assessment (MNA) score
• sarcopenia (measured with computed tomography (CT) fat free mass is reduced; i.e. appendicular\L2 skeletal muscle mass index <7.2 kg/m2 (men) or <5.5 kg/m2 (women));
• cachexia (weight loss (WL)>5% in last 6 months, or WL>2% if body mass index (BMI) <20 kg/m² or sarcopenia);
• 12-item functional assessment of anorexia/cachexia therapy anorexia/cachexia subscale (FAACT-A/CS-12)
• a biliary stent
• a duodenal stent
• total and direct bilirubin
• ECOG status
• European Organization for Research and Treatment of Cancer (EORTC) QLQ-PAN26 scale
• Date of diagnosis, visit 1, visit 2 (3 months), and death/loss from follow up
• Check up on survival at 6m

Tumor-related:

• Tumor site documented by endoscopic ultrasound, CT, or magnetic resonance imaging (head, body, or tail)
• Stage according to the TNM classification
• Vessels involved
• Presence and site of metastatic disease
• Ascites
• CA-19-9
• Response evaluation criteria in solid tumors (RECIST) (for visit 2)

Nutritional parameters:

• Leucocytes (lymphocytes, neutrophils), neutrophil to lymphocytes ratio, erythrocytes, hemoglobin, hematocrit, platelets
• C-reactive protein, total protein, albumin, cholesterol, iron, transferrin, ferritin, magnesium, zinc
• International normalized ratio, activated partial thromboplastin time
• Blood fasting glucose, glycated hemoglobin

Pancreatic function and treatment:

• PEI, fecal elastase-1, pancreatic enzyme replacement therapy (PERT), date of starting PERT, the dosage of daily taken PERT
• Diabetes mellitus (DM), date of DM diagnosis, DM type, DM treatment

Treatment-related:

• Planned chemotherapy protocol Dosages of chemotherapy planned (mg/m2)
• Percent of standard chemotherapy dose delivered
• Percent of planned chemotherapy delivered
• Changes to the predefined schedule (dose reduction, schedule modifications, stop before planned)
• Date of treatment start and end
• Adverse events (National Cancer Institute toxicity scale for visit 2)

Description of the intervention (schedule of visits):

Visit 1 (screening, within 1 month from initial diagnosis). Patients will be informed about the study. Once patients agree with the inclusion in the study the investigators will evaluate the inclusion and exclusion criteria. Those patients who meet all the inclusion criteria and none of the exclusion criteria will be finally included in the study. In this visit, patients, tumor-related variables, and general patients' features will be recorded, and quality of life questionnaire will be administered. The researcher will record weight, height, body mass index (BMI), unplanned WL % for the last 6 months.

Each patient's baseline nutrition status will be evaluated using the MNA scores prior to starting chemotherapy. Patients will be classified as in the group with no nutritional risk, at risk of malnutrition, or malnourished.

Nutritional parameters and pancreatic function will be evaluated through blood tests and a fecal test.

Visit 2 (3 months after the first dose of planned chemotherapy). The researcher will record in the case report form (CRF) the planned chemotherapy, schedule, doses, dose reduction, and any adverse event. The same variables recorded at Visit 1 will be checked again.

Check up 3 (end of the study, 6 months). The researcher will record in the CRF the overall survival and time until progression.

Medication of the study:

The study is of observational nature, so a pre-planned treatment is not considered. However, the use of pancreatic enzyme replacement treatment will be recorded as well as data regarding the employed chemotherapy regimen.

Power size calculation:

The expected percent of chemotherapy delivered in well-nourished patients was based on a study that assessed the chemotherapy dose intensity in gastrointestinal malignancies included pancreaticobiliary disease during the firsts 8 weeks after the start of the chemotherapy23. Based on an expected percentage of chemotherapy delivered of 70% in well-nourished patients, with a type I error of 0.05 and a type II error of 0.20, a sample size of 93 patients per group will be required in case of a percentage difference of chemotherapy delivered of 20% between well-nourished and malnourished, 163 patients per group in case of a difference of 15% between both groups and 356 patients per group in case of 10% of difference.

Discussion:

Given the sparse overall scientific data on the subject, the investigators have designed a study that addresses the impact of patient's nutritional status and dietary intervention on the clinical course of patients with advanced PDAC treated with chemotherapy and is aimed at establishing whether it affects both tolerance and tumor response to medical therapy. PAC-MAIN will be the first study specifically investigating whether the nutritional status influences the possibility to complete planned chemotherapy in patients with advanced PDAC.

Inclusion Criteria:

• age ≥ 18 years;
• histological diagnosis of PDAC within one month from recruitment to the study;
• radiological diagnosis of the advanced stage not suitable for upfront surgical resection (either locally advanced or metastatic) within 5 weeks from recruitment to the study;
• data on the variables and the outcomes of interest are available;
• a written consent to participate in the study;
• being planned for chemotherapy;
• no past history of anticancer treatment.

Exclusion Criteria:

• poor performance status (Eastern Cooperative Oncology Group scale (ECOG) ≥ 3);
• pregnancy;
• surgery for PDAC in the past and developed progression.

patients with unresectable locally advanced or metastatic PDAC